Chronic lymphocytic leukemia (CLL), the most prevalent leukemia in the Western world, is predominantly a disease of older individuals who also have other comorbidities as well as declining organ and bone marrow reserve. Although chemoimmunotherapy is the frontline therapy for ft CLL patients who can tolerate the therapy, many elderly patients cannot tolerate such intense therapy.
Methods
The authors frst reviewed the most recent findings concerning CLL cytogenetics, molecular biology, and prognostic models. They then surveyed recent and ongoing trials of novel CLL agents and strategies, with a focus on those most relevant to elderly patients.
Results
Novel therapies, revised staging procedures, and careful assessment of individual patients’ frailty and functional status will allow clinicians to provide optimal care management for older CLL patients.
Conclusion
Therapy for the elderly CLL population must be tailored to each patient's fitness level and comorbid conditions, with special consideration for the potential quality-of-life impacts of various treatment recommendations.
SwerdlowS.H., CampoE., HarrisN.L.. Chronic lymphocytic leukemia/small lymphocytic lymphoma. In: SwerdlowS.H., CampoE., HarrisN.L.. eds. World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues.Lyon, France: IARC;2008: 180–182.
3.
SiegelR.L., MillerK.D., JemalA.. Cancer statistics, 2015.CA Cancer J Clin.2015; 65: 5–29.
ShanafeltT.D.. Predicting clinical outcome in CLL: how and why.Hematology Am Soc Hematol Educ Program.2009; 421–429.
6.
Pinilla-IbarzJ., McQuaryA.. Chronic lymphocytic leukemia: putting new treatment options into perspective.Cancer Control.2010; 17 (2 suppl): 4–15;quiz 16.
7.
Riches TomblynM.. A review of cellular therapies for chronic lymphocytic leukemia.Biol Blood Marrow Transplant.2014; 20: 164–167.
8.
HallekM., FischerK., Fingerle-RowsonG.. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.Lancet.2010; 376: 1164–1174.
9.
HillmenP., RobakT., JanssensA.. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial.Lancet.2015; 385: 1873–1883.
10.
GoedeV., FischerK., BuschR.. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.N Engl J Med.2014; 370: 1101–1110.
RossiD., SozziE., PumaA.. The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors.Br J Haematol.2009; 146: 64–75.
13.
HallekM., ChesonB.D., CatovskyD.. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines.Blood.2008; 111: 5446–5456.
BinetJ.L., AuquierA., DighieroG.. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.Cancer.1981; 48: 198–206.
16.
RaiK.R.. A critical analysis of staging in CLL. In: GaleR.P., RaiK.R., eds. Chronic Lymphocytic Leukemia: Recent Progress and Future Direction. 1987 UCLA Symposia on Molecular and Cellular Biology, New Series, vol. 59. New York, New York: Alan R Liss; 1987.
17.
HallekM., LangenmayerI., NerlC.. Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia.Blood.1999; 93: 1732–1737.
18.
WierdaW.G., O'BrienS., WangX.. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia.Blood.2007; 109: 4679–4685.
19.
MagnacC., PorcherR., DaviF.. Predictive value of serum thymidine kinase level for Ig-V mutational status in B-CLL.Leukemia.2003; 17: 133–137.
20.
HallekM., WandersL., OstwaldM.. Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma.Leuk Lymphoma.1996; 22: 439–447.
21.
GreverM.R., LucasD.M., DewaldG.W.. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997.J Clin Oncol.2007; 25: 799–804.
22.
HamblinT.J., DavisZ., GardinerA.. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.Blood.1999; 94: 1848–1854.
23.
OscierD.G., ThompsettA., ZhuD.. Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities.Blood.1997; 89: 4153–4160.
24.
LinK.I., TamC.S., KeatingM.J.. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens.Blood.2009; 113: 3168–3171.
25.
DurigJ., NascharM., SchmuckerU.. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia.Leukemia.2002; 16: 30–35.
26.
ChevallierP., PentherD., Avet-LoiseauH.. CD38 expression and secondary 17p deletion are important prognostic factors in chronic lymphocytic leukaemia.Br J Haematol.2002; 116: 142–150.
27.
WiestnerA., RosenwaldA., BarryT.S.. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile.Blood.2003; 101: 4944–4951.
28.
RassentiL.Z., HuynhL., ToyT.L.. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.N Engl J Med.2004; 351: 893–901.
29.
OrchardJ.A., IbbotsonR.E., DavisZ.. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia.Lancet.2004; 363: 105–111.
30.
RoseD.M., HanJ., GinsbergM.H.. Alpha4 integrins and the immune response.Immunol Rev.2002; 186: 118–124.
31.
ZucchettoA., VaisittiT., BenedettiD.. The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells.Leukemia.2012; 26: 1301–1312.
32.
Eksioglu-DemiralpE., AlpdoganO., AktanM.. Variable expression of CD49d antigen in B cell chronic lymphocytic leukemia is related to disease stages.Leukemia.1996; 10: 1331–1339.
33.
GatteiV., BulianP., Del PrincipeM.I.. Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia.Blood.2008; 111: 865–873.
34.
BulianP., ShanafeltT.D., FeganC.. CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia.J Clin Oncol.2014; 32: 897–904.
35.
VogelsteinB., LaneD., LevineA.J.. Surfing the p53 network.Nature.2000; 408: 307–310.
36.
ZenzT., HabeS., DenzelT.. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial.Blood.2009; 114: 2589–2597.
37.
DickerF., HerholzH., SchnittgerS.. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype.Leukemia.2009; 23: 117–124.
38.
ZenzT., EichhorstB., BuschR.. TP53 mutation and survival in chronic lymphocytic leukemia.J Clin Oncol.2010; 28: 4473–4479.
39.
DohnerH., StilgenbauerS., BennerA.. Genomic aberrations and survival in chronic lymphocytic leukemia.N Engl J Med.2000; 343: 1910–1916.
40.
DohnerH., FischerK., BentzM.. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias.Blood.1995; 85: 1580–1589.
41.
DohnerH., StilgenbauerS., JamesM.R.. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis.Blood.1997; 89: 2516–2522.
42.
NeilsonJ.R., AuerR., WhiteD.. Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival.Leukemia.1997; 11: 1929–1932.
43.
TsimberidouA.M., TamC., AbruzzoL.V.. Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia.Cancer.2009; 115: 373–380.
44.
FinkA.M., BöttcherS., RitgenM.. Prediction of poor outcome in CLL patients following first-line treatment with fludarabine, cyclophosphamide and rituximab.Leukemia.2013; 27: 1949–1952.
45.
WangL., LawrenceM.S., WanY.. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia.N Engl J Med.2011; 365: 2497–2506.
46.
FabbriG., RasiS., RossiD.. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.J Exp Med.2011; 208: 1389–1401.
QuesadaV., CondeL., VillamorN.. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.Nat Genet.2012; 44: 47–52.
49.
RossiD., FangazioM., RasiS.. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia.Blood.2012; 119: 2854–2862.
50.
RossiD., RasiS., SpinaV.. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia.Blood.2013; 121: 1403–1412.
51.
Di GiovanniS., ValentiniG., CarducciP.. Beta-2-microglobulin is a reliable tumor marker in chronic lymphocytic leukemia.Acta Haematol.1989; 81: 181–185.
52.
WierdaW.G., O'BrienS., WangX.. Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment.J Clin Oncol.2009; 27: 1637–1643.
53.
CallT.G., NormanA.D., HansonC.A.. Incidence of chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis using the 2008 guidelines.Cancer.2014; 120: 2000–2005.
54.
BulianP., TarnaniM., RossiD.. Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia.Hematol Oncol.2011; 29: 91–99.
55.
GentileM., MauroF.R., RossiD.. Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases.Br J Haematol.2014; 167: 224–232.
56.
PflugN., BahloJ., ShanafeltT.D.. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.Blood.2014; 124: 49–62.
57.
KutschN., BahloJ., ByrdJ.C.. The International Prognostic Index for Patients with CLL (CLL-IPI): An international meta-analysis. Program and abstracts of the 55th American Society of Clinical Oncology Annual Meeting and Exposition; May 29-June 2, 2015; Chicago, Illinois. Abstract 7002.
58.
ChesonB.D., BennettJ.M., GreverM.. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment.Blood.1996; 87: 4990–4997.
59.
ExtermannM., OvercashJ., LymanG.H.. Comorbidity and functional status are independent in older cancer patients.J Clin Oncol.1998; 16: 1582–1587.
60.
BalducciL., ExtermannM.. Management of cancer in the older person: a practical approach.Oncologist.2000; 5: 224–237.
61.
EichhorstB., GoedeV., HallekM.. Treatment of elderly patients with chronic lymphocytic leukemia.Leuk Lymphoma.2009; 50: 171–178.
62.
CramerP., GoedeV., JenkeP.. Impact of different chemotherapy regimen in comorbid patients with advanced chronic lymphocytic leukemia: metaanalysis of two phase-III-trials of the German CLL Study Group. Program and abstracts of the 48th American Society of Hematology Annual Meeting; December 9-12, 2006; Orlando, Florida. Abstract 2840.
63.
ExtermannM., BolerI., ReichR.R.. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score.Cancer.2012; 118: 3377–3386.
EichhorstB., FinkA.M., BuschR.. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an international, randomized study of the German CLL Study Group (GCLLSG).Blood.2013; 122: 526.
66.
EichhorstB., FinkA.M., BuschR.. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study). Program and abstracts of the 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 19.
67.
FischerK., CramerP., BuschR.. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.J Clin Oncol.2012; 30: 3209–3216.
68.
AlduaijW., IvanovA., HoneychurchJ.. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies.Blood.2011; 117: 4519–4529.
69.
O'BrienS., FurmanR.R., CoutreS.E.. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.Lancet Oncol.2014; 15: 48–58.
70.
ByrdJ.C., FurmanR.R., CoutreS.E.. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib.Blood.2015; 125: 2497–2506.
71.
ZelenetzA.D., LamannaN., KippsT.J.. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Program and abstracts of the 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 1986.
72.
O'BrienS.M., LamannaN., KippsT.J.. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3KΣ) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Program and abstracts of the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, Illinois. Abstract 7005.
73.
O'BrienS., LamannaN., KippsT.J.. Update on a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Program and abstracts of the 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 1994.
74.
FurmanR.R., SharmanJ.P., CoutreS.E.. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.N Engl J Med.2014; 370: 997–1007.
75.
ChesonB.D., ByrdJ.C., RaiK.R.. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia.J Clin Oncol.2012; 30: 2820–2822.
